The goal of this project is to carry out a detailed structure-activity study for purposes of exploring the binding site for cocaine at the dopamine transporter (DAT), and also for gaining the knowledge to design potent reversible and irreversible binding ligands. Some earlier structure-activity work indicated large effects of modifications in different parts of the cocaine molecule. Accordingly, a number of studies were undertaken to examine the effects of systematic alterations in the cocaine molecule. In one of these, the 2beta position was varied. It was found that large changes could be made without loss of binding at DAT but the presence of an ester group was desirable. Given that a large variety of structures were possible at this site suggests that this site may be key for modification to produce some irreversible binding probes. In additional studies of the 2beta position, it was observed that utilization of isopropyl and phenyl esters resulted in strikingly enhanced specificity for the dopamine transporter over norepinephrine and serotonin transporters. Also, the iodo-labelled isopropyl ester phenyltropane analog (RTI-121) was found to be the most potent cocaine analog known. In another series of studies we examined changes in the phenyl substituents of phenyltropane compounds. We found that 3,4,dichloro and 4chloro-3methyl compounds were highly potent, exhibiting an IC50 that was 125 times more potent than that of cocaine. The position of the nitrogen atom in the tropane moiety of phenyltropanes was varied. While the nitrogen atom is important for binding to the dopamine transporter, modification of the tropane by moving the nitrogen atom from the 8 to the 6 or 7 position of the azabicyclic ring, there is not a significant loss of binding potency. Thus, significant advances have been made in this area and many new cocaine analogs have been identified. This will impact on several areas of cocaine research.